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Garg AK, Wang J, Alonzo B, Yi J, Kashani AH. Photoreceptor Outer Segment Reflectivity With Ultrahigh-Resolution Visible-Light Optical Coherence Tomography in Systemic Hydroxychloroquine Use. Transl Vis Sci Technol 2025; 14:2. [PMID: 40029247 PMCID: PMC11887931 DOI: 10.1167/tvst.14.3.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/19/2025] [Indexed: 03/05/2025] Open
Abstract
Purpose To evaluate outer retinal organization in normal subjects and those using hydroxychloroquine (HCQ) with ultrahigh-resolution visible-light optical coherence tomography (VIS-OCT). Methods Forty eyes of 22 adult subjects were recruited from a tertiary-care retina practice, including controls (20 eyes, 12 subjects, 40 ± 22 years old) and subjects with a history of HCQ use (20 eyes, 10 subjects, 62 ± 17 years old). Each subject was imaged using a custom-built VIS-OCT device (axial resolution 1.3 µm) and U.S. Food and Drug Administration-approved OCT devices. Results With the use of VIS-OCT, control subjects demonstrated five and six hyperreflective bands in the foveal and parafoveal regions, respectively, between the outer nuclear layer and Bruch's membrane. These bands demonstrated intensity profiles complementary to the known histopathologic distribution of rods and cones. In comparison to controls, subjects taking HCQ demonstrated reduced intensity of all bands, particularly bands two to four. In all cases of suspected or known toxicity, VIS-OCT demonstrated attenuation of band 3i, and in no cases was there attenuation of other bands that was more severe than band 3i, suggesting that changes in the reflectivity of band 3i may be the earliest identifiable sign of HCQ toxicity. Conclusions VIS-OCT of the outer retina revealed a unique outer retinal banding pattern corresponding to photoreceptor density distributions. Notable attenuation of the photoreceptor outer segment reflectivity profile was associated with early HCQ toxicity. This finding may be an early, and possibly reversible, sign of HCQ toxicity, primarily impacting the cones. Translational Relevance VIS-OCT is useful in detecting subclinical outer retinal structural changes found in subjects using hydroxychloroquine.
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Affiliation(s)
- Anupam K. Garg
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Jingyu Wang
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Bailee Alonzo
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Ji Yi
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Amir H. Kashani
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins Hospital, Baltimore, MD, USA
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Garg AK, Wang J, Alonzo B, Yi J, Kashani AH. Photoreceptor outer segment reflectivity with ultrahigh resolution visible light optical coherence tomography in systemic hydroxychloroquine use. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.09.10.24313265. [PMID: 39314959 PMCID: PMC11419217 DOI: 10.1101/2024.09.10.24313265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Purpose To evaluate outer retinal organization in normal subjects and those using hydroxychloroquine (HCQ) with ultrahigh resolution visible light optical coherence tomography (VIS-OCT). Methods Forty eyes of 22 adult subjects were recruited from a tertiary care retina practice including controls (20 eyes, 12 subjects, mean age 40±22yrs, mean logMAR BCVA 0.19, 90% female) and subjects with a history of HCQ use (20 eyes, 10 subjects, mean age 62±17yrs, mean logMAR BCVA 0.03, 67% female). Each subject was imaged using a custom-built VIS-OCT device (axial resolution 1.3μm) and FDA-approved OCT devices. Results Using VIS-OCT, control subjects demonstrate 5 and 6 hyperreflective bands in the foveal and parafoveal regions, respectively, between the outer nuclear layer and Bruch's membrane. These bands demonstrate intensity profiles complementary to the known histopathologic distribution of rods and cones. In comparison to controls, subjects taking HCQ demonstrate blunting of all bands, particularly bands 2-4. In all cases of suspected or known toxicity, VIS-OCT demonstrated attenuation of band 3i and in no cases was there attenuation of other bands that was more severe than band 3i, suggesting that changes in the reflectivity of Band 3i may be the earliest identifiable sign of HCQ toxicity. Conclusions VIS-OCT of the outer retina demonstrates a unique outer retinal banding pattern corresponding to photoreceptor density profiles. There is a notable attenuation of the photoreceptor outer segment reflectivity profile associated with early HCQ toxicity. This finding may be an early, and possibly reversible, sign of HCQ toxicity, primarily impacting the cones.
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Affiliation(s)
- Anupam K. Garg
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Jingyu Wang
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Bailee Alonzo
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Ji Yi
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Amir H. Kashani
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins Hospital, Baltimore, MD, USA
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Sonalcan V, Çakir B, Özkan Aksoy N, Özata Gündoğdu K, Türkoğlu Şen EB, Alagöz G. The assessment of structural and functional test results for early detection of hydroxychloroquine macular toxicity. Int Ophthalmol 2024; 44:370. [PMID: 39237823 DOI: 10.1007/s10792-024-03296-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 08/26/2024] [Indexed: 09/07/2024]
Abstract
PURPOSE To assess structural (optical coherence tomography, fundus autofluorescence) and functional (contrast sensitivity and visual field) test results which were used for detecting early retinal changes in patients using oral hydroxychloroquine. METHODS Patients using oral hydroxychloroquine for at least one year were divided into two groups according to the duration of drug use. Groups 1 and 2 consisted of patients with drug use for more than 5 years and 1-5 years, respectively. The drug-using groups were compared with the control group. The mean retinal nerve fiber layer (RNFL), central macular thickness (CMT), ganglion cell-inner plexiform layer (GC-IPL), static 10-2 visual field, fundus autofluorescence (FAF) imaging, and contrast sensitivity tests were performed and statistically compared between groups. RESULTS Median and temporal quadrant RNFL thicknesses were found to be statistically significantly lower in the drug groups. In the drug groups, the GC-IPL sectoral and mean thicknesses were found to be statistically lower in all quadrants. Central macular thickness was also found to be similar in all three groups. There was no significant difference between the groups in visual field parameters. Macular FAF images were significantly higher in the drug users, but there was no significant difference between the three groups in foveal FAF images. Contrast sensitivity measurements were significantly lower in the drug groups than in the control group at all spatial frequencies except 6 and 18 cycles/degree. CONCLUSIONS The combined use of structural and functional tests in patients using hydroxychloroquine provides useful information in detecting early retinal changes.
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Affiliation(s)
- Vildan Sonalcan
- Department of Ophthalmology, Sakarya University Education and Research Hospital, Sakarya, Turkey
| | - Burçin Çakir
- Department of Ophthalmology, Sakarya University Education and Research Hospital, Sakarya, Turkey
| | - Nilgün Özkan Aksoy
- Department of Ophthalmology, Sakarya University Education and Research Hospital, Sakarya, Turkey
| | - Kübra Özata Gündoğdu
- Department of Ophthalmology, Sakarya University Education and Research Hospital, Sakarya, Turkey.
| | | | - Gürsoy Alagöz
- Department of Ophthalmology, Sakarya University Education and Research Hospital, Sakarya, Turkey
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Meng L, Wang Y, Yang Z, Lin S, Wang Y, Chen H, Zhao X, Chen Y. Ocular fundus changes and association with systemic conditions in systemic lupus erythematosus. Front Immunol 2024; 15:1395609. [PMID: 39091490 PMCID: PMC11291259 DOI: 10.3389/fimmu.2024.1395609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 06/26/2024] [Indexed: 08/04/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and systems. Ocular involvement is estimated to manifest in one-third of individuals with SLE, of which lupus retinopathy and choroidopathy represent the severe subtype accompanied by vision impairment. Advancements in multimodal ophthalmic imaging have allowed ophthalmologists to reveal subclinical microvascular and structural changes in fundus of patients with SLE without ocular manifestations. Both ocular manifestations and subclinical fundus damage have been shown to correlate with SLE disease activity and, in some patients, even precede other systemic injuries as the first presentation of SLE. Moreover, ocular fundus might serve as a window into the state of systemic vasculitis in patients with SLE. Given the similarities of the anatomy, physiological and pathological processes shared among ocular fundus, and other vital organ damage in SLE, such as kidney and brain, it is assumed that ocular fundus involvement has implications in the diagnosis and evaluation of other systemic impairments. Therefore, evaluating the fundus characteristics of patients with SLE not only contributes to the early diagnosis and intervention of potential vision damage, but also holds considerate significance for the evaluation of SLE vasculitis state and prediction of other systemic injuries.
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Affiliation(s)
- Lihui Meng
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Yinhan Wang
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhikun Yang
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Shiqun Lin
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuelin Wang
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Huan Chen
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Xinyu Zhao
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Youxin Chen
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China
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Paredes-Ruiz D, Martin-Iglesias D, Ruiz-Irastorza G. Balancing risks and benefits in the use of hydroxychloroquine and glucocorticoids in systemic lupus erythematosus. Expert Rev Clin Immunol 2024; 20:359-373. [PMID: 38112074 DOI: 10.1080/1744666x.2023.2294938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/08/2023] [Indexed: 12/20/2023]
Abstract
INTRODUCTION Hydroxychloroquine (HCQ) and glucocorticoids (GCs) constitute the oldest and more used drugs in the treatment of systemic lupus erythematosus (SLE). Despite this long experience, both are still subject to a number of uncertainties, mainly regarding the dose. AREAS COVERED We review the main mechanisms of action, the clinical and toxic effects of HCQ and GCs and analyze the recommendations for the use of both in guidelines published since 2018. We offer a set of recommendations based on the pharmacology, mechanisms of action and clinical evidence. EXPERT OPINION HCQ is the backbone therapy for SLE, and a judicious use must be accomplished, using doses that allow a good control of lupus without compromising the safety of treatments very much prolonged over the time. Stable doses of 200 mg/day seem to accomplish both conditions. GCs should be used more judiciously, with methyl-prednisolone pulses as the main therapy for inducing rapid remission and doses ≤5-2.5 mg/day be never exceeded in long-term maintenance treatments.
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Affiliation(s)
- Diana Paredes-Ruiz
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, The Basque Country, Spain
| | - Daniel Martin-Iglesias
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, The Basque Country, Spain
| | - Guillermo Ruiz-Irastorza
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, The Basque Country, Spain
- Department of Medicine, University of the Basque Country, The Basque Country, Spain
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Kim YM, Sung JH, Cha HH, Oh SY. Hydroxychloroquine in obstetrics: potential implications of the prophylactic use of hydroxychloroquine for placental insufficiency during pregnancy. Obstet Gynecol Sci 2024; 67:143-152. [PMID: 38246692 PMCID: PMC10948207 DOI: 10.5468/ogs.23252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 01/23/2024] Open
Abstract
Proper placentation during early pregnancy is a key factor for maintaining a healthy pregnancy. Placental insufficiency leads to critical complications such as preeclampsia, fetal growth restriction, and fetal demise. These complications are often associated with pathological findings of restricted remodeling and obstructive lesions of the myometrial spiral arteries, which have high recurrence rates during subsequent pregnancies. Currently, there are no pharmacological interventions other than aspirin for the prevention of preeclampsia. Hydroxychloroquine (HCQ), a well-known antimalarial drug, reduces inflammatory and thrombotic changes in vessels. For decades, the use of HCQ for autoimmune diseases has resulted in the successful prevention of both arterial and venous thrombotic events and has been extended to the treatment of lupus and antiphospholipid antibody syndrome during pregnancy. HCQ reduces the risk of preeclampsia with lupus by up to 90%. Several recent studies have investigated whether HCQ improves pregnancy outcomes in women with a history of poor outcomes. In addition, in vitro and animal studies have demonstrated the beneficial effects of HCQ in improving endothelial dysfunction and alleviating hypertension and proteinuria. Therefore, we hypothesized that HCQ has the potential to attenuate the vascular inflammatory and thrombogenic pathways associated with placental insufficiency and conducted a multicenter clinical trial on the efficacy of combining aspirin with HCQ for pregnancies at high risk for preeclampsia in Korea. This study summarizes the potential effects of HCQ on pregnancies with placental insufficiency and the implications of HCQ treatment in the field of obstetrics.
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Affiliation(s)
- Yoo-Min Kim
- Department of Obstetrics and Gynecology, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University School of Medicine, Seoul,
Korea
| | - Ji-Hee Sung
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Hyun-Hwa Cha
- Department of Obstetrics and Gynecology, Kyungpook National University Chilgok Hospital, Kyungpook National University School of Medicine, Daegu,
Korea
| | - Soo-Young Oh
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
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Eschbach J, Wagner A, Beahr C, Bekel A, Korganow AS, Quartier A, Peter JC, Eftekhari P. Drug upgrade: A complete methodology from old drug to new chemical entities using Nematic Protein Organization Technique. Drug Dev Res 2024; 85:e22151. [PMID: 38349254 DOI: 10.1002/ddr.22151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/27/2023] [Accepted: 01/03/2024] [Indexed: 02/15/2024]
Abstract
Drug repurposing is used to propose new therapeutic perspectives. Here, we introduce "Drug Upgrade", that is, characterizing the mode of action of an old drug to generate new chemical entities and new therapeutics. We proposed a novel methodology covering target identification to pharmacology validation. As an old drug, we chose hydroxychloroquine (HCQ) for its well-documented clinical efficacy in lupus and its side effect, retinal toxicity. Using the Nematic Protein Organization Technique (NPOT®) followed by liquid chromatography-tandem mass spectrometry analyses, we identified myeloperoxidase (MPO) and alpha-crystallin β chain (CRYAB) as primary and secondary targets to HCQ from lupus patients' peripheral blood mononuclear cells (PBMCs) and isolated human retinas. Surface plasmon resonance (SPR) and enzymatic assays confirmed the interaction of HCQ with MPO and CRYAB. We synthesized INS-072 a novel analog of HCQ that increased affinity for MPO and decreased binding to CRYAB compared to HCQ. INS-072 delayed cutaneous eruption significantly compared to HCQ in the murine MRL/lpr model of spontaneous lupus and prevents immune complex vasculitis in mice. In addition, long-term HCQ treatment caused retinal toxicity in mice, unlike INS-072. Our study illustrates a method of drug development, where new applications or improvements can be explored by fully characterizing the drug's mode of action.
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Affiliation(s)
| | - Alain Wagner
- Bio-Functional Chemistry (UMR 7199), Institut du Médicament de Strasbourg, Illkirch-Graffenstaden, France
- Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France
| | - Corinne Beahr
- Bio-Functional Chemistry (UMR 7199), Institut du Médicament de Strasbourg, Illkirch-Graffenstaden, France
| | - Akkiz Bekel
- Inoviem Scientific, Illkirch-Graffenstaden, France
| | - Anne-Sophie Korganow
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, University Hospital and INSERM UMR 1109, Strasbourg, France
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Rao IR, Kolakemar A, Shenoy SV, Prabhu RA, Nagaraju SP, Rangaswamy D, Bhojaraja MV. Hydroxychloroquine in nephrology: current status and future directions. J Nephrol 2023; 36:2191-2208. [PMID: 37530940 PMCID: PMC10638202 DOI: 10.1007/s40620-023-01733-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 07/03/2023] [Indexed: 08/03/2023]
Abstract
Hydroxychloroquine is one of the oldest disease-modifying anti-rheumatic drugs in clinical use. The drug interferes with lysosomal activity and antigen presentation, inhibits autophagy, and decreases transcription of pro-inflammatory cytokines. Owing to its immunomodulatory, anti-inflammatory, anti-thrombotic effect, hydroxychloroquine has been an integral part of therapy for systemic lupus erythematosus and lupus nephritis for several decades. The therapeutic versatility of hydroxychloroquine has led to repurposing it for other clinical conditions, with recent studies showing reduction in proteinuria in IgA nephropathy. Research is also underway to investigate the efficacy of hydroxychloroquine in primary membranous nephropathy, Alport's syndrome, systemic vasculitis, anti-GBM disease, acute kidney injury and for cardiovascular risk reduction in chronic kidney disease. Hydroxychloroquine is well-tolerated, inexpensive, and widely available and therefore, should its indications expand in the future, it would certainly be welcomed. However, clinicians should be aware of the risk of irreversible and progressive retinal toxicity and rarely, cardiomyopathy. Monitoring hydroxychloroquine levels in blood appears to be a promising tool to evaluate compliance, individualize the dose and reduce the risk of retinal toxicity, although this is not yet standard clinical practice. In this review, we discuss the existing knowledge regarding the mechanism of action of hydroxychloroquine, its utility in lupus nephritis and other kidney diseases, the main adverse effects and the evidence gaps that need to be addressed in future research. Created with Biorender.com. HCQ, hydroxychloroquine; GBM, glomerular basement membrane; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; TLR, toll-like receptor.
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Affiliation(s)
- Indu Ramachandra Rao
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104.
| | - Ashwija Kolakemar
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Srinivas Vinayak Shenoy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Ravindra Attur Prabhu
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Dharshan Rangaswamy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
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Kalaw FGP, Arnett J, Baxter SL, Walker E, Pedersen B, Borooah S. Trends and practices following the 2016 hydroxychloroquine screening guidelines. Sci Rep 2023; 13:15618. [PMID: 37730825 PMCID: PMC10511627 DOI: 10.1038/s41598-023-42816-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 09/14/2023] [Indexed: 09/22/2023] Open
Abstract
This study aimed to understand the profile of hydroxychloroquine-treated patients, referral patterns, and dosing and to assess the adherence of eye care providers to the latest 2016 screening guidelines provided by the American Academy of Ophthalmology. Patients were identified using electronic health records (EHR) taking hydroxychloroquine and were seen by optometrists, retinal specialists, and non-retinal ophthalmologists. Review of EHR data includes demographic characteristics, indications, and dosing profile of hydroxychloroquine use, eye care provider managing the patient, and imaging modalities performed. A total of 166 patients were included in the study. The most common indications for screening were systemic lupus erythematosus and discoid lupus (52.4%) followed by rheumatoid arthritis (18.7%) and Sjögren's syndrome (9.6%). Ninety-two (55.4%) patients were on a higher-than-recommended dose of > 5 mg/kg/day. Patients who weighed less (mean 63.9 kg) were taking a higher-than-recommended dose (vs. 81.5 kg, p < 0.001). Although retinal specialists adhered best to the use of all three recommended imaging modalities, visual field testing was done appropriately for only 8.3% of Asian and 71.1% of non-Asian patients. In conclusion, there is substantial variability in screening by ophthalmic providers and prescribing practices compared with the current recommendations. In particular, there is a marked deficiency in correct visual field testing in Asian patients. These findings are important to highlight potential interventions to improve screening for hydroxychloroquine toxicity.
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Affiliation(s)
- Fritz Gerald P Kalaw
- Viterbi Family Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, 9415, Campus Point Drive, La Jolla, CA, 92093, USA
- Jacobs Retina Center, University of California San Diego, 9415, Campus Point Drive, La Jolla, CA, 92093, USA
- Division of Ophthalmology Informatics and Data Science, Viterbi Family Department of Ophthalmology, 9415 Campus Point Drive, La Jolla, CA, 92093, USA
| | - Justin Arnett
- Viterbi Family Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, 9415, Campus Point Drive, La Jolla, CA, 92093, USA
| | - Sally L Baxter
- Viterbi Family Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, 9415, Campus Point Drive, La Jolla, CA, 92093, USA
- Division of Ophthalmology Informatics and Data Science, Viterbi Family Department of Ophthalmology, 9415 Campus Point Drive, La Jolla, CA, 92093, USA
- Health Department of Biomedical Informatics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Evan Walker
- Viterbi Family Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, 9415, Campus Point Drive, La Jolla, CA, 92093, USA
| | - Brian Pedersen
- Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92161, USA
| | - Shyamanga Borooah
- Viterbi Family Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, 9415, Campus Point Drive, La Jolla, CA, 92093, USA.
- Jacobs Retina Center, University of California San Diego, 9415, Campus Point Drive, La Jolla, CA, 92093, USA.
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Cardoso MH, Hall MJ, Burgoyne T, Fale P, Storm T, Escrevente C, Antas P, Seabra MC, Futter CE. Impaired Lysosome Reformation in Chloroquine-Treated Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci 2023; 64:10. [PMID: 37548963 PMCID: PMC10411645 DOI: 10.1167/iovs.64.11.10] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 07/07/2023] [Indexed: 08/08/2023] Open
Abstract
Purpose To model the in vivo effects of chloroquine on the retinal pigment epithelium in experimentally tractable cell culture systems and determine the effects of mild chloroquine treatment on lysosome function and turnover. Methods Effects of low-dose chloroquine treatment on lysosomal function and accessibility to newly endocytosed cargo were investigated in primary and embryonic stem cell-derived RPE cells and ARPE19 cells using fluorescence and electron microscopy of fluorescent and gold-labeled probes. Lysosomal protein expression and accumulation were measured by quantitative PCR and Western blotting. Results Initial chloroquine-induced lysosome neutralization was followed by partial recovery, lysosomal expansion, and accumulation of undegraded endocytic, phagocytic, and autophagic cargo and inhibition of cathepsin D processing. Accumulation of enlarged lysosomes was accompanied by a gradual loss of accessibility of these structures to the endocytic pathway, implying impaired lysosome reformation. Chloroquine-induced accumulation of pro-cathepsin D, as well as the lysosomal membrane protein, LAMP1, was reproduced by treatment with protease inhibitors and preceded changes in lysosomal gene expression. Conclusions Low-dose chloroquine treatment inhibits lysosome reformation, causing a gradual depletion of lysosomes able to interact with cargo-carrying vacuoles and degrade their content. The resulting accumulation of newly synthesized pro-cathepsin D and LAMP1 reflects inhibition of normal turnover of lysosomal constituents and possibly lysosomes themselves. A better understanding of the mechanisms underlying lysosome reformation may reveal new targets for the treatment of chloroquine-induced retinopathy.
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Affiliation(s)
- M Helena Cardoso
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa; Lisboa, Portugal
| | | | | | - Pedro Fale
- UCL Institute of Ophthalmology, London, United Kingdom
| | - Tina Storm
- UCL Institute of Ophthalmology, London, United Kingdom
| | - Cristina Escrevente
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa; Lisboa, Portugal
| | - Pedro Antas
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa; Lisboa, Portugal
| | - Miguel C Seabra
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa; Lisboa, Portugal
- UCL Institute of Ophthalmology, London, United Kingdom
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Radun V, Berlin A, Tarau IS, Kleefeldt N, Reichel C, Hillenkamp J, Holz FG, Sloan KR, Saßmannshausen M, Ach T. Quantitative Fundus Autofluorescence in Systemic Chloroquine/Hydroxychloroquine Therapy: One Year Follow-Up. Transl Vis Sci Technol 2023; 12:8. [PMID: 37418250 PMCID: PMC10337803 DOI: 10.1167/tvst.12.7.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/08/2023] Open
Abstract
Purpose Systemic chloroquine/hydroxychloroquine (CQ/HCQ) can cause severe ocular side effects including bull's eye maculopathy (BEM). Recently, we reported higher quantitative autofluorescence (QAF) levels in patients with CQ/HCQ intake. Here, QAF in patients taking CQ/HCQ in a 1-year follow-up is reported. Methods Fifty-eight patients currently or previously treated with CQ/HCQ (cumulative doses 94-2435 g) and 32 age- and sex-matched healthy subjects underwent multimodal retinal imaging (infrared, red free, fundus autofluorescence [FAF], QAF [488 nm], and spectral-domain optical coherence tomography (SD-OCT). For analysis, custom written FIJI plugins were used for image processing, multimodal image stacks assembling, and QAF calculation. Results Thirty patients (28 without BEM and 2 with BEM, age range = 25-69 years) were followed up (370 ± 63 days). QAF values in patients taking CQ/HCQ showed a significant increase between baseline and follow-up examination: 282.0 ± 67.9 to 297.7 ± 70.0 (QAF a.u.), P = 0.002. An increase up to 10% was observed in the superior macular hemisphere. Eight individuals (including 1 patient with BEM) had a pronounced QAF increase of up to 25%. Compared to healthy controls, QAF levels in patients taking CQ/HCQ were significantly increased (P = 0.04). Conclusions Our study confirms our previous finding of increased QAF in patients taking CQ/HCQ with a further significant QAF increase from baseline to follow-up. Whether pronounced QAF increase might predispose for rapid progression toward structural changes and BEM development is currently investigated in ongoing studies. Translational Relevance In addition to standard screening tools during systemic CQ/HCQ treatment, QAF imaging might be useful in CQ/HCQ monitoring and could serve as a screening tool in the future.
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Affiliation(s)
- Victoria Radun
- University Hospital Würzburg, Department of Ophthalmology, Würzburg, Germany
| | - Andreas Berlin
- University Hospital Würzburg, Department of Ophthalmology, Würzburg, Germany
| | - Ioana-Sandra Tarau
- University Hospital Würzburg, Department of Ophthalmology, Würzburg, Germany
- Asklepios Hospital Hamburg, Department of Ophthalmology, Hamburg, Germany
| | - Nikolai Kleefeldt
- University Hospital Würzburg, Department of Ophthalmology, Würzburg, Germany
| | - Clara Reichel
- University Hospital Würzburg, Department of Ophthalmology, Würzburg, Germany
| | - Jost Hillenkamp
- University Hospital Würzburg, Department of Ophthalmology, Würzburg, Germany
| | - Frank G Holz
- University Hospital Bonn, Department of Ophthalmology, Bonn, Germany
| | - Kenneth R Sloan
- Asklepios Hospital Hamburg, Department of Ophthalmology, Hamburg, Germany
| | | | - Thomas Ach
- University Hospital Würzburg, Department of Ophthalmology, Würzburg, Germany
- University Hospital Bonn, Department of Ophthalmology, Bonn, Germany
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12
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Liang Z, You G. Chloroquine and Hydroxychloroquine, as Proteasome Inhibitors, Upregulate the Expression and Activity of Organic Anion Transporter 3. Pharmaceutics 2023; 15:1725. [PMID: 37376173 DOI: 10.3390/pharmaceutics15061725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 05/26/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Organic anion transporter 3 (OAT3), at the basolateral membrane of kidney proximal tubule cells, facilitates the elimination of numerous widely used drugs. Earlier investigation from our laboratory revealed that ubiquitin conjugation to OAT3 leads to OAT3 internalization from the cell surface, followed by degradation in the proteasome. In the current study, we examined the roles of chloroquine (CQ) and hydroxychloroquine (HCQ), two well-known anti-malarial drugs, in their action as proteasome inhibitors and their effects on OAT3 ubiquitination, expression, and function. We showed that in cells treated with CQ and HCQ, the ubiquitinated OAT3 was considerably enhanced, which correlated well with a decrease in 20S proteasome activity. Furthermore, in CQ- and HCQ-treated cells, OAT3 expression and OAT3-mediated transport of estrone sulfate, a prototypical substrate, were significantly increased. Such increases in OAT3 expression and transport activity were accompanied by an increase in the maximum transport velocity and a decrease in the degradation rate of the transporter. In conclusion, this study unveiled a novel role of CQ and HCQ in enhancing OAT3 expression and transport activity by preventing the degradation of ubiquitinated OAT3 in proteasomes.
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Affiliation(s)
- Zhengxuan Liang
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Guofeng You
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
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13
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Yusuf IH, Charbel Issa P, Ahn SJ. Hydroxychloroquine-induced Retinal Toxicity. Front Pharmacol 2023; 14:1196783. [PMID: 37324471 PMCID: PMC10267834 DOI: 10.3389/fphar.2023.1196783] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/17/2023] [Indexed: 06/17/2023] Open
Abstract
Long-term use of hydroxychloroquine can cause retinopathy, which may result in severe and progressive visual loss. In the past decade, hydroxychloroquine use has markedly increased and modern retinal imaging techniques have enabled the detection of early, pre-symptomatic disease. As a consequence, the prevalence of retinal toxicity in long-term hydroxychloroquine users is known to be higher than was previously estimated. The pathophysiology of the retinopathy is incompletely characterised, although significant advances have been made in understanding the disease from clinical imaging studies. Hydroxychloroquine retinopathy elicits sufficient public health concern to justify the implementation of retinopathy screening programs for patients at risk. Here, we describe the historical background of hydroxychloroquine retinopathy and summarize its current understanding. We review the utility and limitations of each of the mainstream diagnostic tests used to detect hydroxychloroquine retinopathy. The key considerations towards a consensus on the definition of hydroxychloroquine retinopathy are outlined in the context of what is known of the natural history of the disease. We compare the current screening recommendations for hydroxychloroquine retinopathy, identifying where additional evidence is required, and the management of proven cases of toxicity. Finally, we highlight the areas for further investigation, which may further reduce the risk of visual loss in hydroxychloroquine users.
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Affiliation(s)
- Imran H. Yusuf
- Oxford Eye Hospital and Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Peter Charbel Issa
- Oxford Eye Hospital and Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Seong Joon Ahn
- Department of Ophthalmology, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, South Korea
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14
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Cheong KX, Ong CJT, Chandrasekaran PR, Zhao J, Teo KYC, Mathur R. Review of Retinal Imaging Modalities for Hydroxychloroquine Retinopathy. Diagnostics (Basel) 2023; 13:diagnostics13101752. [PMID: 37238236 DOI: 10.3390/diagnostics13101752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/10/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
This review provides an overview of conventional and novel retinal imaging modalities for hydroxychloroquine (HCQ) retinopathy. HCQ retinopathy is a form of toxic retinopathy resulting from HCQ use for a variety of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Each imaging modality detects a different aspect of HCQ retinopathy and shows a unique complement of structural changes. Conventionally, spectral-domain optical coherence tomography (SD-OCT), which shows loss or attenuation of the outer retina and/or retinal pigment epithelium-Bruch's membrane complex, and fundus autofluorescence (FAF), which shows parafoveal or pericentral abnormalities, are used to assess HCQ retinopathy. Additionally, several variations of OCT (retinal and choroidal thickness measurements, choroidal vascularity index, widefield OCT, en face imaging, minimum intensity analysis, and artificial intelligence techniques) and FAF techniques (quantitative FAF, near-infrared FAF, fluorescence lifetime imaging ophthalmoscopy, and widefield FAF) have been applied to assess HCQ retinopathy. Other novel retinal imaging techniques that are being studied for early detection of HCQ retinopathy include OCT angiography, multicolour imaging, adaptive optics, and retromode imaging, although further testing is required for validation.
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Affiliation(s)
- Kai Xiong Cheong
- Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore
| | - Charles Jit Teng Ong
- Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore
| | - Priya R Chandrasekaran
- Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore
| | - Jinzhi Zhao
- Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore
| | - Kelvin Yi Chong Teo
- Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore 169857, Singapore
| | - Ranjana Mathur
- Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore 169857, Singapore
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15
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Sarkar S, Singh PC. Selective Action of Antimalarial Hydroxychloroquine on the Packing of Phospholipids and Interfacial Water Associated with Lysosomal Model Membranes: A Vibrational Sum Frequency Generation Study. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2023; 39:2435-2443. [PMID: 36735290 DOI: 10.1021/acs.langmuir.2c03321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Understanding the structural change of lysosomal membranes induced by hydroxychloroquine (HCQ) drug is essential as it has been considered as one of the probable mechanisms of its antimalarial action. In this context, vibrational sum frequency generation (VSFG) spectra of the O-H region of water and C-H of the hydrocarbon chain of negatively charged and zwitterionic phospholipids associated with the lysosomal membrane in the absence and presence of different concentrations of HCQ have been measured at the air/water interface. The interfacial water at the negatively charged and zwitterionic lipids gets restructured in the presence of HCQ; however, the mechanism of restructuring is different due to the charge of the head groups of lipids. Interestingly, the presence of HCQ leads to a disorder in the negatively charged lipids, irrespective of their chemical nature, mainly by creating the gauche defect in the hydrocarbon chain of the lipid. In contrast, the ordering of the zwitterionic lipid does not show any appreciable change with the addition of HCQ. The finding on the selectivity of HCQ in affecting the ordering of the lipid depending on its head group charge and restructuring of interfacial water may be useful in understanding the molecular level mechanism of the antimalarial action of HCQ.
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Affiliation(s)
- Sunipa Sarkar
- School of Chemical Sciences, Indian Association for the Cultivation of Science, Kolkata700032, India
| | - Prashant Chandra Singh
- School of Chemical Sciences, Indian Association for the Cultivation of Science, Kolkata700032, India
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16
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Rosin B, Sahel J. Lifting the iron curtain of vision. EMBO Mol Med 2023; 15:e17259. [PMID: 36715217 PMCID: PMC9906325 DOI: 10.15252/emmm.202217259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/31/2023] Open
Abstract
Ocular and specifically retinal toxicities of systemic medications are prevalent and encompass many disease modalities. For many of these pharmaceuticals, established follow-up protocols are in place to ensure timely detection and cessation of therapy. However, while for some disorders, cessation of therapy is a viable option due to existing treatment alternatives, for some others cessation of treatment can be life threatening and/or shorten the patient's life expectancy. Such is the case for iron chelating agents used in transfusion-dependent patients of Thalassemia, of which deferoxamine (DFO) is the most widely used. In their recent article in EMBO Molecular Medicine, Kong et al (2023) addressed the issue of DFO-induced retinal toxicity used both in vivo and in vitro techniques. Their study suggests a potentially protective role for α-ketoglutarate (AKG) supplementation against DFO toxicity.
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Affiliation(s)
- Boris Rosin
- Department of Ophthalmology/UPMC Eye CenterUniversity of PittsburghPittsburghPAUSA
| | - Jose‐Alain Sahel
- Department of Ophthalmology/UPMC Eye CenterUniversity of PittsburghPittsburghPAUSA
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17
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Zhu XY, Tang XH, Yu H. Amiodarone-induced muscle tremor in an elderly patient: A case report. World J Clin Cases 2022; 10:12726-12733. [PMID: 36579101 PMCID: PMC9791518 DOI: 10.12998/wjcc.v10.i34.12726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/09/2022] [Accepted: 11/04/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Amiodarone is a Class III antiarrhythmic drug, which has been adopted for the treatment of atrial fibrillation and ventricular arrhythmia. However, the use of amiodarone can cause lower limb muscle tremors, which is recognized as a rare side effect of this medication.
CASE SUMMARY An 84-year-old female was administrated with amiodarone for paroxysmal supraventricular tachycardia and frequent ventricular tachycardia. The patient developed a bilateral gastrocnemius tremor in the course of medication, and the strength of the patient’s bilateral knee flexor and extensor reached 4/5 and 3/5, respectively. After the use of amiodarone was stopped, and the patient was given a small dose of levetiracetam, the lower limb tremor symptoms were significantly mitigated, along with activity and function.
CONCLUSION Attention should be paid to the significance of the side effects of drugs in the elderly, which may be atypical in the elderly. The relevant side effects of drugs may not be as rare as reported due to individual differences and different pharmacokinetics. If the side effects are generated, the medication should be adjusted in time, and the progress of the side effects should be intervened.
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Affiliation(s)
- Xiao-Yong Zhu
- Department of Cardiology, Jiujiang University Affiliated Hospital, Jiujiang 332000, Jiangxi Province, China
| | - Xin-Hu Tang
- Department of Cardiology, Jiujiang University Affiliated Hospital, Jiujiang 332000, Jiangxi Province, China
| | - Hua Yu
- Department of Cardiology, Jiujiang University Affiliated Hospital, Jiujiang 332000, Jiangxi Province, China
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18
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Niemann B, Puleo A, Stout C, Markel J, Boone BA. Biologic Functions of Hydroxychloroquine in Disease: From COVID-19 to Cancer. Pharmaceutics 2022; 14:pharmaceutics14122551. [PMID: 36559044 PMCID: PMC9787624 DOI: 10.3390/pharmaceutics14122551] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/05/2022] [Accepted: 11/10/2022] [Indexed: 11/23/2022] Open
Abstract
Chloroquine (CQ) and Hydroxychloroquine (HCQ), initially utilized in the treatment of malaria, have now developed a long list of applications. Despite their clinical relevance, their mechanisms of action are not clearly defined. Major pathways by which these agents are proposed to function include alkalinization of lysosomes and endosomes, downregulation of C-X-C chemokine receptor type 4 (CXCR4) expression, high-mobility group box 1 protein (HMGB1) inhibition, alteration of intracellular calcium, and prevention of thrombus formation. However, there is conflicting data present in the literature. This is likely the result of the complex overlapping pathways between these mechanisms of action that have not previously been highlighted. In fact, prior research has focused on very specific portions of particular pathways without describing these in the context of the extensive CQ/HCQ literature. This review summarizes the detailed data regarding CQ/HCQ's mechanisms of action while also providing insight into the overarching themes. Furthermore, this review provides clinical context to the application of these diverse drugs including their role in malaria, autoimmune disorders, cardiovascular disease, thrombus formation, malignancies, and viral infections.
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Affiliation(s)
- Britney Niemann
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
- Correspondence: ; Tel.: +1-304-293-1254
| | - Amanda Puleo
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
| | - Conley Stout
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
| | - Justin Markel
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
| | - Brian A. Boone
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506, USA
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19
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Parrulli S, Cozzi M, Airaldi M, Romano F, Viola F, Sarzi‐Puttini P, Staurenghi G, Invernizzi A. Quantitative autofluorescence findings in patients undergoing hydroxychloroquine treatment. Clin Exp Ophthalmol 2022; 50:500-509. [PMID: 35503294 PMCID: PMC9545387 DOI: 10.1111/ceo.14090] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 04/27/2022] [Accepted: 04/29/2022] [Indexed: 11/28/2022]
Abstract
Background Methods Results Conclusions
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Affiliation(s)
- Salvatore Parrulli
- Eye Clinic, Department of Biomedical and Clinical Science “Luigi Sacco”, Sacco Hospital University of Milan Milan Italy
| | - Mariano Cozzi
- Eye Clinic, Department of Biomedical and Clinical Science “Luigi Sacco”, Sacco Hospital University of Milan Milan Italy
| | - Matteo Airaldi
- Eye Clinic, Department of Biomedical and Clinical Science “Luigi Sacco”, Sacco Hospital University of Milan Milan Italy
| | - Francesco Romano
- Eye Clinic, Department of Biomedical and Clinical Science “Luigi Sacco”, Sacco Hospital University of Milan Milan Italy
| | - Francesco Viola
- Ophthalmological Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan Italy
- Department of Clinical Sciences and Community Health University of Milan Milan Italy
| | | | - Giovanni Staurenghi
- Eye Clinic, Department of Biomedical and Clinical Science “Luigi Sacco”, Sacco Hospital University of Milan Milan Italy
| | - Alessandro Invernizzi
- Eye Clinic, Department of Biomedical and Clinical Science “Luigi Sacco”, Sacco Hospital University of Milan Milan Italy
- The University of Sydney, Save Sight Institute, Discipline of Ophthalmology Sydney Medical School Sydney New South Wales Australia
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20
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Kavanagh ON, Bhattacharya S, Marchetti L, Elmes R, O’Sullivan F, Farragher JP, Robinson S, Thompson D, Walker GM. Hydroxychloroquine Does Not Function as a Direct Zinc Ionophore. Pharmaceutics 2022; 14:pharmaceutics14050899. [PMID: 35631485 PMCID: PMC9147311 DOI: 10.3390/pharmaceutics14050899] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/11/2022] [Accepted: 04/15/2022] [Indexed: 02/04/2023] Open
Abstract
Drug-mediated correction of abnormal biological zinc homeostasis could provide new routes to treating neurodegeneration, cancer, and viral infections. Designing therapeutics to facilitate zinc transport intracellularly is hampered by inadequate concentrations of endogenous zinc, which is often protein-bound in vivo. We found strong evidence that hydroxychloroquine, a drug used to treat malaria and employed as a potential treatment for COVID-19, does not bind and transport zinc across biological membranes through ionophoric mechanisms, contrary to recent claims. In vitro complexation studies and liposomal transport assays are correlated with cellular zinc assays in A549 lung epithelial cells to confirm the indirect mechanism of hydroxychloroquine-mediated elevation in intracellular zinc without ionophorism. Molecular simulations show hydroxychloroquine-triggered helix perturbation in zinc-finger protein without zinc chelation, a potential alternative non-ionophoric mechanism.
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Affiliation(s)
- Oisín N. Kavanagh
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
- School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
- Department of Chemical Sciences, Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
- Department of Chemistry, Maynooth University (National University of Ireland), W23 F2H6 Maynooth, Ireland
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
- Correspondence:
| | - Shayon Bhattacharya
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
- Department of Physics, Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
| | - Luke Marchetti
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
- Department of Chemistry, Maynooth University (National University of Ireland), W23 F2H6 Maynooth, Ireland
| | - Robert Elmes
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
- Department of Chemistry, Maynooth University (National University of Ireland), W23 F2H6 Maynooth, Ireland
| | - Finbarr O’Sullivan
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - John P. Farragher
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
| | - Shane Robinson
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
- Janssen Pharmaceutical Sciences, T45 P663 Cork, Ireland
| | - Damien Thompson
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
- Department of Physics, Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
| | - Gavin M. Walker
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (S.B.); (L.M.); (R.E.); (F.O.); (J.P.F.); (S.R.); (D.T.); (G.M.W.)
- Department of Chemical Sciences, Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
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21
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Yazdani M. Uncontrolled Oxygen Levels in Cultures of Retinal Pigment Epithelium: Have We Missed the Obvious? Curr Eye Res 2022; 47:651-660. [PMID: 35243933 DOI: 10.1080/02713683.2022.2050264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Retinal pigment epithelium (RPE) is the outermost layer of retina located between the photoreceptor cells and the choroid. This highly-polarized monolayer provides critical support for the functioning of the other parts of the retina, especially photoreceptors. Methods of culturing RPE have been under development since its establishment in 1920s. Despite considering various factors, oxygen (O2) levels in RPE microenvironments during culture preparation and experimental procedure have been overlooked. O2 is a crucial parameter in the cultures, and therefore, maintaining RPE cells at O2 levels different from their native environment (70-90 mm Hg of O2) could have unintended consequences. Owing to the importance of the topic, lack of sufficient discussion in the literature and to encourage future research, this paper will focus on uncontrolled O2 level in cultures of RPE cells.
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Affiliation(s)
- Mazyar Yazdani
- Department of Medical Biochemistry, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway
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22
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Robinson G, Pineda-Torra I, Ciurtin C, Jury EC. Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies. J Clin Invest 2022; 132:e148552. [PMID: 35040437 PMCID: PMC8759788 DOI: 10.1172/jci148552] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.
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Affiliation(s)
- George Robinson
- Centre for Rheumatology Research
- Centre for Adolescent Rheumatology Research, and
| | - Ines Pineda-Torra
- Centre for Cardiometabolic and Vascular Science, Division of Medicine, University College London, London, United Kingdom
| | - Coziana Ciurtin
- Centre for Rheumatology Research
- Centre for Adolescent Rheumatology Research, and
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23
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Chen Y, Zhu X, Ye F, Wang H, Wan X, Zhang T, Wang Y, Wang Y, Zhao X, Bai X, Xiao Y, Sun X. Malondialdehyde-Modified Photoreceptor Outer Segments Promote Choroidal Neovascularization in Mice. Transl Vis Sci Technol 2022; 11:12. [PMID: 35015060 PMCID: PMC8762676 DOI: 10.1167/tvst.11.1.12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose This study aimed to establish a novel choroidal neovascularization (CNV) mouse model through subretinally injecting malondialdehyde (MDA)-modified photoreceptor outer segments (POS), which was more consistent with the pathogenesis of wet age-related macular degeneration (AMD). Methods MDA-modified POS were subretinally injected in C57BL/6J mice. Four weeks later, to assess the volume of CNV and the morphology of retinal pigment epithelium (RPE), isolectin B4 and zonula occludens-1 antibody were used for immunostaining. Fundus fluorescent angiography and optical coherence tomography imaging were used to describe the morphologic features of CNV. Transepithelial resistance was measured on polarized ARPE-19 cells. Vascular endothelial growth factor levels in the cell culture medium were detected by enzyme-linked immunosorbent assay. The protein and messenger RNA expression levels of autophagy markers were measured using Western blot and quantitative polymerase chain reaction. Results CNV and RPE atrophy were successfully induced in the mouse model. MDA-modified POS also significantly increased the expression of vascular endothelial growth factor and disrupted cell junctions in RPE cells. In addition, MDA-modified POS induced autophagy–lysosomal impairment in RPE cells. Conclusions Subretinal injection of MDA-modified POS may generate a feasible CNV model that simulates the AMD pathological process. Translational Relevance This study expands the understanding of the role of MDA in AMD pathogenesis, which provides a potential therapeutic target of AMD.
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Affiliation(s)
- Yuhong Chen
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Xinyue Zhu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Fuxiang Ye
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Hong Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Xiaoling Wan
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Fundus Diseases, Shanghai, China
| | - Ting Zhang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Fundus Diseases, Shanghai, China
| | - Yuwei Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Yimin Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Xiaohuan Zhao
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Xinyue Bai
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Yushu Xiao
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Xiaodong Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
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24
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Sato R, Imaizumi T, Aizawa T, Watanabe S, Tsugawa K, Kawaguchi S, Seya K, Matsumiya T, Tanaka H. Inhibitory effect of anti-malarial agents on the expression of proinflammatory chemokines via Toll-like receptor 3 signaling in human glomerular endothelial cells. Ren Fail 2021; 43:643-650. [PMID: 33820486 PMCID: PMC8032345 DOI: 10.1080/0886022x.2021.1908901] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/24/2021] [Accepted: 03/14/2021] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE Although anti-malarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ) are currently used for the treatment of systemic lupus erythematosus, their efficacy for lupus nephritis (LN) remains unclear. Given that upregulation of glomerular Toll-like receptor 3 (TLR3) signaling plays a pivotal role in the pathogenesis of LN, we examined whether CQ and HCQ affect the expression of the TLR3 signaling-induced representative proinflammatory chemokines, monocyte chemoattractant protein-1 (MCP-1), and C-C motif chemokine ligand 5 (CCL5) in cultured human glomerular endothelial cells (GECs). METHODS We examined the effect of polyinosinic-polycytidylic acid (poly IC), an agonist of TLR3, on MCP-1, CCL5 and interferon (IFN)-β expression in GECs. We then analyzed whether pretreatment with CQ, HCQ, or dexamethasone (DEX) inhibits poly IC-induced expression of these chemokines using real-time quantitative reverse transcriptase PCR and ELISA. Phosphorylation of signal transducers and activator of transcription protein 1 (STAT1) was examined using western blotting. RESULTS Poly IC increased MCP-1 and CCL5 expression in a time- and concentration-dependent manner in GECs. Pretreating cells with CQ, but not DEX, attenuated poly IC-induced MCP-1 and CCL5 expression; however, HCQ pretreatment attenuated poly IC-induced CCL5, but not MCP-1. HCQ did not affect the expression of IFN-β and phosphorylation of STAT-1. CONCLUSION Considering that TLR3 signaling is implicated, at least in part, in LN pathogenesis, our results suggest that anti-malarial agents exert a protective effect against the development of inflammation in GECs, as postulated in LN. Interestingly, CQ is a rather powerful inhibitor compared with HCQ on TLR3 signaling-induced chemokine expression in GECs. In turn, these findings may further support the theory that the use of HCQ is safer than CQ in a clinical setting. However, further detailed studies are needed to confirm our preliminary findings.
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Affiliation(s)
- Riko Sato
- Department of Pediatrics, Hirosaki University Hospital, Hirosaki, Japan
| | - Tadaatsu Imaizumi
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tomomi Aizawa
- Department of Pediatrics, Hirosaki University Hospital, Hirosaki, Japan
| | - Shojiro Watanabe
- Department of Pediatrics, Hirosaki University Hospital, Hirosaki, Japan
| | - Koji Tsugawa
- Department of Pediatrics, Hirosaki University Hospital, Hirosaki, Japan
| | - Shogo Kawaguchi
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Kazuhiko Seya
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tomoh Matsumiya
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hiroshi Tanaka
- Department of Pediatrics, Hirosaki University Hospital, Hirosaki, Japan
- Faculty of Education, Department of School Health Science, Hirosaki University, Hirosaki, Japan
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25
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Kavanagh O, Elmes R, O’Sullivan F, Farragher J, Robinson S, Walker G. Investigating Structural Property Relationships to Enable Repurposing of Pharmaceuticals as Zinc Ionophores. Pharmaceutics 2021; 13:2032. [PMID: 34959313 PMCID: PMC8704213 DOI: 10.3390/pharmaceutics13122032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
The importance of zinc in biology has gained greater recognition in recent years due to its essential contributions to the function of many endogenous enzymes. Disruption of zinc homeostasis may be useful in treating pathological conditions, such as Alzheimer's, and for antiviral purposes. Despite the growth of knowledge and increased interest in zinc, little is known about the structure and function of zinc ionophores. In this study we analyse the Cambridge Structural Database and solution complexation studies found in the literature to identify key functional groups which may confer zinc ionophorism. Pharmaceuticals, nutraceuticals and amino acids with these functionalities were selected to enable us to explore the translatability of ionophoric activity from in vitro assays to cellular systems. We find that although certain species may complex to zinc in the solid and solution states, and may carry ions across simple membrane systems, this does not necessarily translate into ionophoric activity. We propose that the CSD can help refine key functionalities but that ionophoric activity must be confirmed in cellular systems.
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Affiliation(s)
- Oisín Kavanagh
- SSPC, The SFI Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (R.E.); (F.O.); (J.F.); (S.R.)
- School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
- School of Chemical Sciences, Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
- Department of Chemistry, Maynooth University, National University of Ireland, W23 F2H6 Maynooth, Ireland
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - Robert Elmes
- SSPC, The SFI Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (R.E.); (F.O.); (J.F.); (S.R.)
- Department of Chemistry, Maynooth University, National University of Ireland, W23 F2H6 Maynooth, Ireland
| | - Finbarr O’Sullivan
- SSPC, The SFI Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (R.E.); (F.O.); (J.F.); (S.R.)
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - John Farragher
- SSPC, The SFI Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (R.E.); (F.O.); (J.F.); (S.R.)
| | - Shane Robinson
- SSPC, The SFI Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (R.E.); (F.O.); (J.F.); (S.R.)
- Janssen Pharmaceutical Sciences, T45 P663 Cork, Ireland
| | - Gavin Walker
- SSPC, The SFI Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland; (R.E.); (F.O.); (J.F.); (S.R.)
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26
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Hydroxychloroquine's Early Impact on Cone Density. J Ophthalmol 2021; 2021:1389805. [PMID: 34527374 PMCID: PMC8437653 DOI: 10.1155/2021/1389805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/26/2021] [Accepted: 08/30/2021] [Indexed: 11/18/2022] Open
Abstract
Purpose To evaluate early effects of hydroxychloroquine (HCQ) on the retina using adaptive optics (AO). Methods This was a prospective observational single-center study of 29 eyes of 29 patients who had been treated with HCQ for the first time and followed with AO for a minimum of two years. Cone counting was performed in 4 quadrants, nasal, temporal, superior, and inferior, at 0.75 mm from the foveal center. The changes of cone density on AO, visual acuity, and foveal thickness within two years of use were analyzed. The changes of mean cone density of patients whose cumulative dose was over 200 g in 2 years were also assessed. We evaluated the correlation between cone density and cumulative dose of HCQ. Results There was no significant decrease in cone density in the first 2 years of HCQ use. VA and foveal thickness did not show obvious change, either. Among 9 patients whose cumulative dose was over 200 g in 2 years, the mean cone density showed no significant change at 6, 12, 18, and 24 months compared with baseline (P=0.381, P=0.380, P=0.281, and P=0.534, respectively). There was no correlation between cone density and cumulative dose of HCQ at two years (Spearman's correlation coefficient, r = −0.0553, P=0.780; n = 29). Conclusion AO showed no change in cone density in the first two years of HCQ use.
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27
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Boudoux O, Toure M, Laurent B, Quintyn JC. [Ophthalmic follow-up of patients treated with antimalarial drugs: Evaluation of patient attitudes regarding the change in protocol]. J Fr Ophtalmol 2021; 44:e493-e496. [PMID: 34353665 DOI: 10.1016/j.jfo.2021.02.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/20/2021] [Accepted: 02/08/2021] [Indexed: 11/26/2022]
Affiliation(s)
- O Boudoux
- Service d'ophtalmologie du CHU de Caen, Université de Caen, Normandie, France; CHU de Caen, avenue de la Côte de Nacre, 14033 Caen, France.
| | - M Toure
- Service d'ophtalmologie du CHU de Caen, Université de Caen, Normandie, France
| | - B Laurent
- Service d'ophtalmologie du CHU de Caen, Université de Caen, Normandie, France
| | - J-C Quintyn
- Service d'ophtalmologie du CHU de Caen, Université de Caen, Normandie, France
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28
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Altulea D, Maassen S, Baranov MV, van den Bogaart G. What makes (hydroxy)chloroquine ineffective against COVID-19: insights from cell biology. J Mol Cell Biol 2021; 13:175-184. [PMID: 33693723 PMCID: PMC7989365 DOI: 10.1093/jmcb/mjab016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 02/17/2021] [Accepted: 02/24/2021] [Indexed: 12/11/2022] Open
Abstract
Since chloroquine (CQ) and hydroxychloroquine (HCQ) can inhibit the invasion and proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured cells, the repurposing of these antimalarial drugs was considered a promising strategy for treatment and prevention of coronavirus disease (COVID-19). However, despite promising preliminary findings, many clinical trials showed neither significant therapeutic nor prophylactic benefits of CQ and HCQ against COVID-19. Here, we aim to answer the question of why these drugs are not effective against the disease by examining the cellular working mechanisms of CQ and HCQ in prevention of SARS-CoV-2 infections.
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Affiliation(s)
- Dania Altulea
- Department of Molecular Immunology and Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands
| | - Sjors Maassen
- Department of Molecular Immunology and Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands
| | - Maksim V Baranov
- Department of Molecular Immunology and Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands
| | - G van den Bogaart
- Department of Molecular Immunology and Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands.,Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
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29
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Yao M, Wu Y, Cao Y, Liu H, Ma N, Chai Y, Zhang S, Zhang H, Nong L, Liang L, Zhang B. Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells. Front Oncol 2021; 11:667920. [PMID: 34123836 PMCID: PMC8189927 DOI: 10.3389/fonc.2021.667920] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/06/2021] [Indexed: 01/22/2023] Open
Abstract
The cGAS (GMP-AMP synthase)-mediated senescence-associated secretory phenotype (SASP) and DNA-induced autophagy (DNA autophagy) have been extensively investigated in recent years. However, cGAS-mediated autophagy has not been elucidated in cancer cells. The described investigation revealed that active DNA autophagy but not SASP activity could be detected in the BT-549 breast cancer cell line with high micronucleus (MN) formation. DNA autophagy was identified as selective autophagy of free genomic DNA in the cytoplasm but not nucleophagy. The process of DNA autophagy in the cytosol could be initiate by cGAS and usually cooperates with SQSTM1-mediated autophagy of ubiquitinated histones. Cytoplasmic DNA, together with nuclear proteins such as histones, could be derived from DNA replication-induced nuclear damage and MN collapse. The inhibition of autophagy through chemical inhibitors as well as the genomic silencing of cGAS or SQSTM1 could suppress the growth and survival of cancer cells, and induced DNA damage could increase the sensitivity to these inhibitors. Furthermore, expanded observations of several other kinds of human cancer cells indicated that high relative DNA autophagy or enhancement of DNA damage could also increase or sensitize these cells to inhibition of DNA autophagy.
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Affiliation(s)
- Mengfei Yao
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yaqian Wu
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yanan Cao
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Haijing Liu
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Ningning Ma
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yijie Chai
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Shuang Zhang
- Department of Pathology, Peking University First Hospital, Beijing, China
| | - Hong Zhang
- Department of Pathology, Peking University First Hospital, Beijing, China
| | - Lin Nong
- Department of Pathology, Peking University First Hospital, Beijing, China
| | - Li Liang
- Department of Pathology, Peking University First Hospital, Beijing, China
| | - Bo Zhang
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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30
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Sallam MA, Beltagi AS, Abdellatif MA, Awadalla MA. Visual Impact of Early Hydroxychloroquine-Related Retinal Structural Changes in Patients with Systemic Lupus Erythematosus. Ophthalmologica 2021; 244:301-308. [PMID: 34015786 DOI: 10.1159/000517090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 05/05/2021] [Indexed: 11/19/2022]
Abstract
PURPOSE The aim of the study was to assess the early retinal structural changes due to hydroxychloroquine (HCQ) use and its impact on visual acuity (VA) of patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS The study was conducted as a case-control study that included 60 eyes of 30 SLE patients treated with HCQ compared with 50 eyes of 25 healthy individuals. Patients were kept on 200 or 400 mg as daily maintenance dose. SLE patients were subgrouped into patients with normal VA and patients with decreased VA. All participants were assessed by the optical coherence tomography (OCT), and early structural abnormalities were recorded. The main outcomes and measures were best-corrected VA, drug exposure time, central macular thickness (CMT), inner segment-outer segment (IS-OS) junction disruption, ganglion cell complex † (GCC†, ganglion cell layer + inner plexiform layer), ganglion cell complex †† (GCC††, nerve fiber layer + GCC†), and peripapillary retinal nerve fiber layer. The characteristics of HCQ retinal toxicity were correlated to VA. RESULTS All OCT parameters were found to be significantly lower (p < 0.001) in HCQ patients with decreased VA than in controls. Patients receiving a daily dose of 400 mg had lower (p < 0.05) parameters than those receiving 200 mg. Patients with IS-OS disruption had lower CMT, GCC †, and GCC †† than those without (p < 0.05). VA was significantly correlated (p < 0.05) with CMT and drug exposure time. CONCLUSIONS The HCQ use caused OCT changes that precede clinically visible retinopathy and might be associated with slight VA reduction. Screening with OCT of patients receiving HCQ is essential to detect early vision loss.
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Affiliation(s)
- Moataz A Sallam
- Ophthalmology Department, Suez Canal University Hospitals, Ismailia, Egypt
| | - Arwa S Beltagi
- Rheumatology Department, Suez Canal University Hospitals, Ismailia, Egypt
| | - Mai A Abdellatif
- Rheumatology Department, Suez Canal University Hospitals, Ismailia, Egypt
| | - Magdy A Awadalla
- Rheumatology Department, Suez Canal University Hospitals, Ismailia, Egypt
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31
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Fetz AE, Wallace SE, Bowlin GL. Electrospun Polydioxanone Loaded With Chloroquine Modulates Template-Induced NET Release and Inflammatory Responses From Human Neutrophils. Front Bioeng Biotechnol 2021; 9:652055. [PMID: 33987174 PMCID: PMC8111017 DOI: 10.3389/fbioe.2021.652055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/19/2021] [Indexed: 12/11/2022] Open
Abstract
The implantation of a biomaterial quickly initiates a tissue repair program initially characterized by a neutrophil influx. During the acute inflammatory response, neutrophils release neutrophil extracellular traps (NETs) and secrete soluble signals to modulate the tissue environment. In this work, we evaluated chloroquine diphosphate, an antimalarial with immunomodulatory and antithrombotic effects, as an electrospun biomaterial additive to regulate neutrophil-mediated inflammation. Electrospinning of polydioxanone was optimized for rapid chloroquine elution within 1 h, and acute neutrophil-biomaterial interactions were evaluated in vitro with fresh human peripheral blood neutrophils at 3 and 6 h before quantifying the release of NETs and secretion of inflammatory and regenerative factors. Our results indicate that chloroquine suppresses NET release in a biomaterial surface area–dependent manner at the early time point, whereas it modulates signal secretion at both early and late time points. More specifically, chloroquine elution down-regulates interleukin 8 (IL-8) and matrix metalloproteinase nine secretion while up-regulating hepatocyte growth factor, vascular endothelial growth factor A, and IL-22 secretion, suggesting a potential shift toward a resolving neutrophil phenotype. Our novel repurposing of chloroquine as a biomaterial additive may therefore have synergistic, immunomodulatory effects that are advantageous for biomaterial-guided in situ tissue regeneration applications.
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Affiliation(s)
- Allison E Fetz
- Department of Biomedical Engineering, University of Memphis, Memphis, TN, United States
| | - Shannon E Wallace
- Department of Biomedical Engineering, University of Memphis, Memphis, TN, United States
| | - Gary L Bowlin
- Department of Biomedical Engineering, University of Memphis, Memphis, TN, United States
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Systemic toxicity of chloroquine and hydroxychloroquine: prevalence, mechanisms, risk factors, prognostic and screening possibilities. Rheumatol Int 2021; 41:1189-1202. [PMID: 33893862 PMCID: PMC8064887 DOI: 10.1007/s00296-021-04868-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023]
Abstract
Chloroquine (CQ) and its hydroxylated analog, hydroxychloroquine (HCQ), are 4-aminoquinoline initially used as an antimalarial treatment. CQ and HCQ (4-aminoquinoline, 4-AQ) are today used in rheumatology, especially to treat rheumatoid arthritis and systemic lupus erythematosus. Their mechanism of action revolves around a singular triptych: 4-AQ acts as alkalizing agents, ionized amphiphilic molecules, and by binding to numerous targets. 4-AQ have so pleiotropic and original mechanisms of action, providing them an effect at the heart of the regulation of several physiological functions. However, this broad spectrum of action is also at the origin of various and original side effects, notably a remarkable chronic systemic toxicity. We describe here the 4-AQ-induced lesions on the eye, the heart, muscle, the nerves, the inner ear, and the kidney. We also describe their prevalence, their pathophysiological mechanisms, their risk factors, their potential severity, and the means to detect them early. Most of these side effects are reversible if treatment is stopped promptly. This 4-AQ-induced toxicity must be known to prescribing physicians, to closely monitor its appearance and stop treatment in time if necessary.
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Uddin E, Islam R, Ashrafuzzaman, Bitu NA, Hossain MS, Islam AN, Asraf A, Hossen F, Mohapatra RK, Kudrat-E-Zahan M. Potential Drugs for the Treatment of COVID-19: Synthesis, Brief History and Application. Curr Drug Res Rev 2021; 13:184-202. [PMID: 34126913 DOI: 10.2174/2589977513666210611155426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 02/02/2021] [Accepted: 03/04/2021] [Indexed: 11/22/2022]
Abstract
Coronaviruses (CoVs) belong to the Betacoronavirus group, an unusually large RNA genome characterized by club-like spikes that project from their surface. An outbreak of a novel coronavirus 2019 (nCOVID-19) already showed a unique replication strategy and infection that has posed significant threat to international health and the economy around the globe. Scientists around the world are investigating few previously used clinical drugs for the treatment of COVID-19. This review provides synthesis and mode of action of recently investigated drugs like Chloroquine, Hydroxychloroquine, Ivermectin, Selamectin, Remdesivir, Baricitinib, Darunavir, Favipiravir, Lopinavir/ ritonavir and Mefloquine hydrochloride that constitute an option for COVID-19 treatment.
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Affiliation(s)
- Ekhlass Uddin
- Department of Chemistry, Rajshahi University, Rajshahi 6205, Bangladesh
| | - Raisul Islam
- Department of Chemistry, Rajshahi University, Rajshahi 6205, Bangladesh
| | - Ashrafuzzaman
- Department of Chemistry, Rajshahi University, Rajshahi 6205, Bangladesh
| | - Nur Amin Bitu
- Department of Chemistry, Rajshahi University, Rajshahi 6205, Bangladesh
| | - Md Saddam Hossain
- Department of Chemistry, Begum Rokeya University, Rangpur, Bangladesh
| | - Abm Nazmul Islam
- Chemistry Discipline, Khulna University, Khulna-9208, Bangladesh
| | - Ali Asraf
- Department of Chemistry, Rajshahi University, Rajshahi 6205, Bangladesh
| | - Faruk Hossen
- Department of Chemistry, Rajshahi University, Rajshahi 6205, Bangladesh
| | - Ranjan K Mohapatra
- Department of Chemistry, Government College of Engineering, Keonjhar, Odisha, India
| | - Md Kudrat-E-Zahan
- Department of Chemistry, Rajshahi University, Rajshahi 6205, Bangladesh
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Chan C, Foster ST, Chan KG, Cacace MJ, Ladd SL, Sandum CT, Wright PT, Volmert B, Yang W, Aguirre A, Li W, Wright NT. Repositioned Drugs for COVID-19-the Impact on Multiple Organs. SN COMPREHENSIVE CLINICAL MEDICINE 2021; 3:1484-1501. [PMID: 33898925 PMCID: PMC8057921 DOI: 10.1007/s42399-021-00874-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 03/22/2021] [Indexed: 02/02/2023]
Abstract
This review summarizes published findings of the beneficial and harmful effects on the heart, lungs, immune system, kidney, liver, and central nervous system of 47 drugs that have been proposed to treat COVID-19. Many of the repurposed drugs were chosen for their benefits to the pulmonary system, as well as immunosuppressive and anti-inflammatory effects. However, these drugs have mixed effects on the heart, liver, kidney, and central nervous system. Drug treatments are critical in the fight against COVID-19, along with vaccines and public health protocols. Drug treatments are particularly needed as variants of the SARS-Cov-2 virus emerge with some mutations that could diminish the efficacy of the vaccines. Patients with comorbidities are more likely to require hospitalization and greater interventions. The combination of treating severe COVID-19 symptoms in the presence of comorbidities underscores the importance of understanding the effects of potential COVID-19 treatments on other organs. Supplementary Information The online version contains supplementary material available at 10.1007/s42399-021-00874-8.
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Affiliation(s)
- Christina Chan
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA ,Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI USA ,Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Sean T. Foster
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Kayla G. Chan
- Integrative Neuroscience Program, Binghamton University, Binghamton, NY USA
| | - Matthew J. Cacace
- Department of Mechanical Engineering, The Pennsylvania State University, University Park, PA USA
| | - Shay L. Ladd
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Caleb T. Sandum
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Paul T. Wright
- Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA USA
| | - Brett Volmert
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Weiyang Yang
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA ,Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Aitor Aguirre
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Wen Li
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA ,Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Neil T. Wright
- Department of Mechanical Engineering, Michigan State University, East Lansing, MI USA
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Marshall E, Robertson M, Kam S, Penwarden A, Riga P, Davies N. Prevalence of hydroxychloroquine retinopathy using 2018 Royal College of Ophthalmologists diagnostic criteria. Eye (Lond) 2021; 35:343-348. [PMID: 32587388 PMCID: PMC7316164 DOI: 10.1038/s41433-020-1038-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/01/2020] [Accepted: 06/09/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION To measure the prevalence of hydroxychloroquine retinopathy in patients attending a hydroxychloroquine monitoring service using 2018 Royal College of Ophthalmologists diagnostic criteria. METHODS A service evaluation audit of a hydroxychloroquine retinopathy monitoring service was undertaken. Results of Humphrey 10-2 field tests, spectral-domain optical coherence tomography and fundus autofluorescence were collected with data on dose, weight, duration of treatment, estimated glomerular filtration rate, and concurrent tamoxifen therapy. Visual field tests were assessed as reliable or unreliable, and classified as normal, hydroxychloroquine-like, poor test or related to other pathology. Cases of definite and possible retinopathy were identified using the 2018 RCOphth criteria. RESULTS There were 1976 attendances over two years of 1597 patients. Seven hundred and twenty-eight patients had taken hydroxychloroquine for less than 5 years and 869 had taken hydroxychloroquine for 5 years or more. Fourteen patients were identified with definite hydroxychloroquine retinopathy (1.6%), and 41 patients with possible retinopathy (4.7%). Sixty-seven per cent of 861 visual fields were performed reliably, with 66.9% classified as normal, 24.9% as poor test, 5.2% hydroxychloroquine-like and 3.0% abnormal due to other pathology. CONCLUSIONS The 1.6% prevalence of hydroxychloroquine retinopathy is lower than the previously reported prevalence of 7.5% as reported by Melles and Marmor JAMA Ophthalmol 132: 1453-60 (2014). This is because of a difference in the diagnostic criteria. Both definite and possible retinopathy would meet the diagnostic criteria of the Melles and Marmor study; 6.3% in our data, compared with 7.5%, a much smaller difference and likely to be explained by differences in the risk characteristics of the two groups.
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Affiliation(s)
- Elena Marshall
- Department of Ophthalmology, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK
| | - Matt Robertson
- Department of Ophthalmology, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK
| | - Satu Kam
- Department of Ophthalmology, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK
| | - Alison Penwarden
- Department of Ophthalmology, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK
| | - Paraskevi Riga
- Department of Ophthalmology, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK
| | - Nigel Davies
- Department of Ophthalmology, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK.
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Saha BK, Bonnier A, Chong W. Antimalarials as Antivirals for COVID-19: Believe it or Not! Am J Med Sci 2020; 360:618-630. [PMID: 32950177 PMCID: PMC7419247 DOI: 10.1016/j.amjms.2020.08.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 08/09/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for the coronavirus disease -19 (COVID-19). Since December 2019, SARS-CoV-2 has infected millions of people worldwide, leaving hundreds of thousands dead. Chloroquine (CQ) and Hydroxychloroquine (HCQ) are antimalarial medications that have been found to have in vitro efficacy against SARS-CoV-2. Several small prospective studies have shown positive outcomes. However, this result has not been universal, and concerns have been raised regarding the indiscriminate use and potential side effects. The clinicians are conflicted regarding the usage of these medications. Appropriate dose and duration of therapy are unknown. Here, we will discuss the pharmacokinetic and pharmacodynamic properties of CQ and HCQ, as well as review the antiviral properties. The manuscript will also examine the available data from recent clinical and preclinical trials in order to shed light on the apparent inconsistencies.
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Affiliation(s)
- Biplab K Saha
- Pulmonary and Critical Care Medicine, Ozarks Medical Center, West Plains, Missouri.
| | - Alyssa Bonnier
- Division of Critical Care Nursing, Goldfarb School of Nursing, Barnes Jewish College, St. Louis, Missouri
| | - Woon Chong
- Division of Pulmonary and Critical Care Medicine, Albany Medical Center College, Albany, New York
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Lei ZN, Wu ZX, Dong S, Yang DH, Zhang L, Ke Z, Zou C, Chen ZS. Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19. Pharmacol Ther 2020; 216:107672. [PMID: 32910933 PMCID: PMC7476892 DOI: 10.1016/j.pharmthera.2020.107672] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022]
Abstract
Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been commonly used for the treatment and prevention of malaria, and the treatment of autoimmune diseases for several decades. As their new mechanisms of actions are identified in recent years, CQ and HCQ have wider therapeutic applications, one of which is to treat viral infectious diseases. Since the pandemic of the coronavirus disease 2019 (COVID-19), CQ and HCQ have been subjected to a number of in vitro and in vivo tests, and their therapeutic prospects for COVID-19 have been proposed. In this article, the applications and mechanisms of action of CQ and HCQ in their conventional fields of anti-malaria and anti-rheumatism, as well as their repurposing prospects in anti-virus are reviewed. The current trials and future potential of CQ and HCQ in combating COVID-19 are discussed.
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Affiliation(s)
- Zi-Ning Lei
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
| | - Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
| | - Shaowei Dong
- Key Laboratory of medical electrophysiology of education ministry, School of Pharmacy, Southwest Medical University, China; Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Southern University of Science and Technology, Shenzhen 518020, Guangdong, China
| | - Dong-Hua Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
| | - Litu Zhang
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zunfu Ke
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
| | - Chang Zou
- Key Laboratory of medical electrophysiology of education ministry, School of Pharmacy, Southwest Medical University, China; Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Southern University of Science and Technology, Shenzhen 518020, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
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Carrière F, Longhi S, Record M. The endosomal lipid bis(monoacylglycero) phosphate as a potential key player in the mechanism of action of chloroquine against SARS-COV-2 and other enveloped viruses hijacking the endocytic pathway. Biochimie 2020; 179:237-246. [PMID: 32485205 PMCID: PMC7261073 DOI: 10.1016/j.biochi.2020.05.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023]
Abstract
The anti-malarial drug Chloroquine (CQ) and its derivative hydroxychloroquine have shown antiviral activities in vitro against many viruses, including coronaviruses, dengue virus and the biosafety level 4 Nipah and Hendra paramyxoviruses. The in vivo efficacy of CQ in the treatment of COVID-19 is currently a matter of debate. CQ is a lysosomotrophic compound that accumulates in lysosomes, as well as in food vacuoles of Plasmodium falciparum. In the treatment of malaria, CQ impairs the digestion and growth of the parasite by increasing the pH of the food vacuole. Similarly, it is assumed that the antiviral effects of CQ results from the increase of lysosome pH and the inhibition of acidic proteases involved in the maturation of virus fusion protein. CQ has however other effects, among which phospholipidosis, characterized by the accumulation of multivesicular bodies within the cell. The increase in phospholipid species particularly concerns bis(monoacylglycero)phosphate (BMP), a specific lipid of late endosomes involved in vesicular trafficking and pH-dependent vesicle budding. It was shown previously that drugs like progesterone, the cationic amphiphile U18666A and the phospholipase inhibitor methyl arachidonyl fluoro phosphonate (MAFP) induce the accumulation of BMP in THP-1 cells and decrease cell infection by human immunodeficiency virus. HIV viral particles were found to be retained into large endosomal-type vesicles, preventing virus spreading. Since BMP was also reported to favour virus entry through hijacking of the endocytic pathway, we propose here that BMP could play a dual role in viral infection, with its antiviral effects triggered by lysosomotropic drugs like CQ.
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Affiliation(s)
- Frédéric Carrière
- Aix Marseille Univ, CNRS, BIP, UMR7281, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 9, France.
| | - Sonia Longhi
- Aix Marseille Univ, CNRS, AFMB, UMR7257, 163 Avenue de Luminy, 13288, Marseille cedex 09, France
| | - Michel Record
- UMR INSERM 1037-CRCT (Cancer Research Center of Toulouse), University of Toulouse III Paul Sabatier, Team "Cholesterol Metabolism and Therapeutic Innovations,", 2 Avenue Hubert Curien, 31037, Toulouse cedex 1, France.
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Paniri A, Hosseini MM, Rasoulinejad A, Akhavan-Niaki H. Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations. Eur J Pharmacol 2020; 886:173454. [PMID: 32763298 PMCID: PMC7402235 DOI: 10.1016/j.ejphar.2020.173454] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 01/07/2023]
Abstract
Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.
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Affiliation(s)
- Alireza Paniri
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Genetics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | | | - Ahmad Rasoulinejad
- Department of Ophthalmology, Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran.
| | - Haleh Akhavan-Niaki
- Genetics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran; Zoonoses Research Center, Pasteur Institute of Iran, Amol, Iran.
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Greenstein VC, Lima de Carvalho JR, Parmann R, Amaro-Quireza L, Lee W, Hood DC, Tsang SH, Sparrow JR. Quantitative Fundus Autofluorescence in HCQ Retinopathy. Invest Ophthalmol Vis Sci 2020; 61:41. [PMID: 32976563 PMCID: PMC7521180 DOI: 10.1167/iovs.61.11.41] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 07/31/2020] [Indexed: 01/23/2023] Open
Abstract
Purpose To increase our understanding of the mechanisms underlying hydroxychloroquine (HCQ) retinopathy, analyses by quantitative fundus autofluorescence (qAF) and near-infrared fundus autofluorescence (NIR-AF) were compared to results obtained by recommended screening tests. Methods Thirty-one patients (28 females, 3 males) were evaluated with standard automated perimetry and spectral domain optical coherence tomography (SD-OCT); 28 also had multifocal electroretinography (mfERG). Measurement of short-wavelength fundus autofluorescence (SW-AF) by qAF involved the use of an internal fluorescent reference and intensity measurements in eight concentric segments at 7° to 9° eccentricity. For semiquantitative analysis of NIR-AF, intensities were acquired along a vertical axis through the fovea. Results Four of 15 high-dose (total dose >1000 g, daily dose >5.0 mg/kg) patients and one of 16 low-dose (total dose <1000 g, daily dose 4.4 mg/kg) patients were diagnosed with HCQ-associated retinopathy based on abnormal 10-2 visual fields, SD-OCT, and SW-AF imaging. Three of the high-dose patients also had abnormal mfERG results. Of the five patients exhibiting retinopathy, two had qAF color-coded images revealing higher intensities inferior, nasal, and lateral to the fovea. The abnormal visual fields also exhibited superior-inferior differences. Mean NIR-AF gray-level intensities were increased in four high-dose patients with no evidence of retinopathy. In two patients with retinopathy, NIR-AF intensity within the parafovea was below the normal range. One high-dose patient (6.25 mg/kg) had only abnormal mfERG results. Conclusions These findings indicate that screening for HCQ retinopathy should take into consideration superior-inferior differences in susceptibility to HCQ retinopathy.
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Affiliation(s)
- Vivienne C. Greenstein
- Department of Ophthalmology, Columbia University Medical Center, New York, New York, United States
- Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
| | | | - Rait Parmann
- Department of Ophthalmology, Columbia University Medical Center, New York, New York, United States
| | - Luz Amaro-Quireza
- Department of Ophthalmology, Columbia University Medical Center, New York, New York, United States
| | - Winston Lee
- Department of Ophthalmology, Columbia University Medical Center, New York, New York, United States
| | - Donald C. Hood
- Department of Ophthalmology, Columbia University Medical Center, New York, New York, United States
- Deparment of Psychology, Columbia University, New York, New York, United States
| | - Stephen H. Tsang
- Department of Ophthalmology, Columbia University Medical Center, New York, New York, United States
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States
| | - Janet R. Sparrow
- Department of Ophthalmology, Columbia University Medical Center, New York, New York, United States
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States
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Li JH, Xu ZY, Li MJ, Zheng WL, Huang XM, Xiao F, Cui YH, Pan HW. LC-MS based metabolomics reveals metabolic pathway disturbance in retinal pigment epithelial cells exposed to hydroxychloroquine. Chem Biol Interact 2020; 328:109212. [DOI: 10.1016/j.cbi.2020.109212] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/13/2020] [Accepted: 07/23/2020] [Indexed: 01/08/2023]
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Sethi A, Bach H. Evaluation of Current Therapies for COVID-19 Treatment. Microorganisms 2020; 8:E1097. [PMID: 32707942 PMCID: PMC7463960 DOI: 10.3390/microorganisms8081097] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 12/12/2022] Open
Abstract
The virus SARS-CoV-2, the etiological agent of COVID-19, is responsible for more than 400,000 deaths worldwide as of 10 June 2020. As a result of its recent appearance (December 2019), an efficacious treatment is not yet available. Although considered a lung infection since its emergence, COVID-19 is now causing multiple organ failure, requiring a continuous adjustment in the procedures. In this review, we summarize the current literature surrounding unproven therapies for COVID-19. Analyses of the clinical trials were grouped as chemotherapy, serotherapy, anticoagulant, and the use of human recombinant soluble ACE2 therapies. We conclude that, while no agent has hit the threshold for quality of evidence to demonstrate efficacy and safety, preliminary data show potential benefits. Moreover, there is a possibility for harm with these unproven therapies, and the decision to treat should be based on a comprehensive risk-benefit analysis.
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Affiliation(s)
- Atin Sethi
- Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada;
| | - Horacio Bach
- Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC ADD ED8, Canada
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Pahan P, Pahan K. Smooth or Risky Revisit of an Old Malaria Drug for COVID-19? J Neuroimmune Pharmacol 2020; 15:174-180. [PMID: 32415419 PMCID: PMC7225253 DOI: 10.1007/s11481-020-09923-w] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 05/04/2020] [Indexed: 02/06/2023]
Abstract
Hydroxychloroquine (HCQ) is an old medication for malaria. In addition to handling this parasitic disease, HCQ is also used to treat a number of autoimmune disorders including rheumatoid arthritis and systemic lupus erythematosus when other medications are not effective. Recently a new viral infection (COVID-19) is rocking the entire world so much that it has already taken more than 200,000 lives throughout the world within the last two months and the World Health Organization was forced to declare it as a pandemic on March 11, 2020. Interestingly, some reports indicate that this wonder drug may be also beneficial for COVID-19 and accordingly, many clinical trials have begun. Here, we discuss different modes of action (anti-inflammatory, antioxidant, inhibition of endosomal acidification, suppression of angiotensin-converting enzyme 2 or ACE2 glycosylation, etc.) of HCQ that might be responsible for its possible anti-COVID-19 effect. On the other hand, this review also makes an honest attempt to delineate mechanisms (increase in vasoconstriction, inhibition of autophagy, depletion of T cells, etc.) indicating how it may aggravate certain conditions and why caution should be taken before granting widespread repurposing of HCQ for COVID-19.
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